WO1994013663A1 - Heterocycles non aromatiques substitues par aminomethylene et leur utilisation comme antagonistes de substance p - Google Patents
Heterocycles non aromatiques substitues par aminomethylene et leur utilisation comme antagonistes de substance p Download PDFInfo
- Publication number
- WO1994013663A1 WO1994013663A1 PCT/US1993/009407 US9309407W WO9413663A1 WO 1994013663 A1 WO1994013663 A1 WO 1994013663A1 US 9309407 W US9309407 W US 9309407W WO 9413663 A1 WO9413663 A1 WO 9413663A1
- Authority
- WO
- WIPO (PCT)
- Prior art keywords
- alkyl
- methoxy
- formula
- phenyl
- amine
- Prior art date
Links
Classifications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D401/00—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom
- C07D401/02—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings
- C07D401/12—Heterocyclic compounds containing two or more hetero rings, having nitrogen atoms as the only ring hetero atoms, at least one ring being a six-membered ring with only one nitrogen atom containing two hetero rings linked by a chain containing hetero atoms as chain links
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/04—Centrally acting analgesics, e.g. opioids
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/18—Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/20—Hypnotics; Sedatives
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/24—Antidepressants
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P25/00—Drugs for disorders of the nervous system
- A61P25/26—Psychostimulants, e.g. nicotine, cocaine
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P37/00—Drugs for immunological or allergic disorders
- A61P37/08—Antiallergic agents
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P9/00—Drugs for disorders of the cardiovascular system
- A61P9/08—Vasodilators for multiple indications
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07D—HETEROCYCLIC COMPOUNDS
- C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
- C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
- C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
Definitions
- the present invention relates to novel aminomethylene substituted non-aromatic heterocycles, pharmaceutical compositions comprising such compounds and the use of such compounds in the treatment and prevention of inflammatory and central nervous system disorders, as well as several other disorders.
- the pharmaceutically active compounds of this invention are substance P receptor antagonists.
- This invention also relates to novel intermediates used in the synthesis of such substance P receptor antagonists.
- Substance P is a naturally occurring undecapeptide belonging to the tachykinin family of peptides, the latter being named because of their prompt stimulatory action on smooth muscle tissue. More specifically, substance P is a pharmacologically active neuropeptide that is produced in mammals and possesses a characteristic amino acid sequence that is illustrated by D. F. Veber et al. in U.S. Patent No. 4,680,283.
- the present invention relates to compounds of the formula a
- A is a ring system selected from phenyl, naphthyl, thienyl, quinolinyl and indolinyl, and wherein the side chain containing NR 2 R 3 is attached to a carbon atom of ring system A;
- W is hydrogen, (C 1 -C 6 )alkyl optionally substituted with from one to three fluorine atoms, -S(O) v -(C 1 -C 6 ) alkyl wherein v is zero, one or two, halo, benzyloxy or (C 1 -C 6 )alkoxy optionally substituted with from one to three fluorine atoms;
- R 1 is a 4, 5 or 6 membered heterocyclic ring containing from one to three heteroatoms selected from oxygen, nitrogen and sulfur (e.g., thiazolyl, azetidinyl, pyrrolyl, pyrazolyl, 1,2,3-triazolyl, 1,2,4-triazolyl, isothiazolyl, imidazolyl, isoxazolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazolyl or thiophenyl), wherein said heterocyclic ring may contain from zero to three double bonds and may optionally be substituted with one or more substituents, preferably one or two substituents, independently selected from (C 1 -C 6 ) alkyl optionally substituted with from one to three fluorine atoms and (C 1 -C 6 ) alkoxy optionally substituted with from one to three fluorine atoms;
- thiazolyl azetidinyl,
- R 2 is hydrogen or -CO 2 (C 1 -C 10 ) alkyl
- R 3 is selected from
- R 6 and R 10 are independently selected from furyl, thienyl, pyridyl, indolyl, biphenyl and phenyl, wherein said phenyl may optionally be substituted with one or two substituents independently selected from halo, (C 1 - C 10 ) alkyl optionally substituted with from one to three fluorine atoms, (C 1 -C 10 ) alkoxy optionally substituted with from one to three fluorine atoms, carboxy, benzyloxycarbonyl and (C 1 -C 3 ) alkoxy-carbonyl;
- R 4 is (C 1 -C 6 ) alkyl or phenyl
- R 7 is selected from (C 3 -C 4 ) branched alkyl, (C 5 -C 6 ) branched alkenyl, (C 5 -C 7 ) cycloalkyl, and the radicals named in the definition of R 6 ;
- R 8 is hydrogen or (C 1 -C 6 ) alkyl
- R 9 and R 19 are independently selected from phenyl, biphenyl, naphthyl, pyridyl, benzhydryl, thienyl and furyl, and R 9 and R 19 may optionally be substituted with from one to three substituents independently selected from halo, (C 1 -C 10 ) alkyl optionally substituted with from one to three fluorine atoms and (C 1 -C 10 ) alkoxy optionally substituted with from one to three fluorine atoms;
- Y is (CH 2 ), wherein 1 is an integer from one to three, or Y is a group of the formula
- Z is oxygen, sulfur, amino, (C 1 -C 3 )alkylamino or (CH 2 ) n . wherein n is zero, one or two;
- x is zero, one or two
- y is zero, one or two
- z is three, four or five;
- o is two or three
- p is zero or one
- r is one, two or thrre; the ring containing (CH 2 ) z may contain from zero to three double bonds, and one of the carbon atoms of (CH 2 ) z may optionally be replaced by oxygen, sulfur or nitrogen;
- R 11 is thienyl, biphenyl or phenyl optionally substituted with one or two substituents independently selected from halo, (C 1 -C 10 ) alkyl optionally substituted with from one to three fluorine atoms and (C 1 -C 10 ) alkoxy optionally substituted with from one to three fluorine atoms;
- X is (CH 2 ) q wherein q is an integer from 1 to 6, and wherein any one of the carbon-carbon single bonds in said
- (CH 2 ) q may optionally be replaced by a carbon-carbon double bond, and wherein any one of the carbon atoms of said (CH 2 ) q may optionally be substituted with R 14 , and wherein any one of the carbon atoms of said (CH 2 ) q may optionally be substituted with R 15 ;
- m is an integer from 0 to 8, and any one of the carbon-carbon single bonds of (CH 2 ) m , wherein both carbon atoms of such bond are bonded to each other and to another carbon atom of the (CH 2 ) m chain, may optionally be replaced by a carbon-carbon double bond or a carbon-carbon triple bond, and any one of the carbon atoms of said (CH 2 ) m may optionally be substituted with R 17 ;
- R 12 is a radical selected from hydrogen, (C 1 -C 6 ) straight or branched alkyl, (C 3 -C 7 ) cycloalkyl wherein one of the carbon atoms may optionally be replaced by nitrogen, oxygen or sulfur; aryl selected from biphenyl, phenyl, indanyl and naphthyl; heteroaryl selected from thienyl, furyl, pyridyl, thiazolyl, isothiazolyl, oxazolyl, isoxazolyl, triazolyl, tetrazolyl and quinolyl; phenyl-(C 2 -C 6 ) alkyl, benzhydryl and benzyl, wherein the point of attachment on R 12 is a carbon atom unless R 12 is hydrogen, and wherein each of said aryl and heteroaryl groups and the phenyl moieties of said benzyl, phenyl-(C 2 -C 6 ) alkyl
- R 13 is hydrogen, phenyl or (C 1 -C 6 ) alkyl
- R 12 and R 13 together with the carbon to which they are attached, form a saturated carbocyclic ring having from 3 to 7 carbon atoms wherein one of said carbon atoms that is neither the point of attachment of the spiro ring nor adjacent to such point of attachment may optionally be replaced by oxygen, nitrogen or sulfur;
- R 16 is NHCR 18 , NHCH 2 R 18 , SO 2 R 18 , CO 2 H or one of the radicals set forth in any of the definitions of R 12 , R 14 and R 15 ;
- R 18 is (C 1 -C 6 ) alkyl, hydrogen, phenyl or phenyl (C 1 - C 6 ) alkyl;
- each of R 14 and R 15 is independently selected from hydrogen, fluoro, (C 1 -C 6 )alkyl, hydroxy- (C 1 -C 6 )alkyl and (C 1 -C 6 ) alkoxy- (C 1 -C 6 ) alkyl, or R 14 and R 15 , together with the carbon to which they are attached, form a (C 3 -C 6 ) saturated carbocyclic ring that forms a spiro compound with the nitrogen-containing ring to which they are attached; (d) R 12 and R 13 can not both be hydrogen, and (e) when R 14 or R 15 is attached to a carbon atom of X or (CH 2 ) y that is
- the present invention also relates to the pharmaceutically acceptable acid addition and base salts of compounds of the formulae Ia and lb (hereinafter referred to, collectively, as compounds of the formula I).
- the acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1'-methylene-bis
- the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula I.
- Such non- toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium calcium and magnesium, etc.
- the fused bicyclic nucleus of compounds of the formula lb to which W and the -CH 2 NR 2 R 3 sidechain are attached may be, but is not limited to one of the following groups: benzoxazolyl, benzthiazolyl, benzimidazolyl, benzisoxazolyl, benzoisothiazolyl, indazolyl, indolyl, isoquinolinyl, benzofuryl, benzothienyl, oxindolyl, benzoxazolinonyl, benzthiazolinonyl, benzimidazolinonyl, benzimidazoliniminyl, dihydrobenzothienyl-S, S-dioxide, benztriazolyl, benzthiadiazolyl, benzoxadiazolyl, and quinazolinyl.
- halo as used herein, unless otherwise indicated, includes chloro, fluoro, bromo and iodo.
- alkyl as used herein, unless otherwise indicated, includes saturated monovalent hydrocarbon radicals having straight, branched or cyclic moieties or combinations thereof.
- alkoxy includes O-alkyl groups wherein “alkyl” is defined as above.
- substituents includes from one to the maximum number of substituents possible based on the number of available bonding sites.
- Preferred compounds of this invention include those compounds of the formula I wherein the substituents at positions "2" and “3" of the nitrogen containing ring of R 3 are in a cis configuration.
- R 3 is a group of the formula VII or VIII
- "a cis configuration" means that the non-hydrogen substituent at position "3" is cis to R 12 .
- R 3 is a group of the formula III, VII or IX;
- R 2 is hydrogen;
- A is phenyl or indolinyl;
- W is (C 1 -C 3 ) alkoxy optionally substituted with from one to five fluorine atoms;
- R 1 is thiazolyl, imidazolyl, thiadiazolyl, pyrrolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazolyl or thiophenyl, and R 1 may optionally be substituted with one or two (C 1 -C 3 ) alkyl moieties.
- R 3 is a group of the formula III, VII or IX
- R 2 is hydrogen
- the fused bicyclic ring system to which W and the -CH 2 NR 2 R 3 sidechain are attached is benzoxazolyl, benzisoxazolyl, benzthiazolyl, benzthiophenyl or benzimidazolyl
- W is (C 1 -C 6 )alkoxy optionally substituted with from one to five fluorine atoms.
- R 3 is a group of the formula III and R 9 is benzhydryl
- R 3 is a group of the formula VII, R 12 is phenyl, each of R 13 , R 14 , R 15 and R 16 is hydrogen, m is zero and X is -(CH 2 ) 3 -; or
- R 3 is a group of the formula IX, r is two and R 19 is benzhydryl.
- R 3 is a group of the formula III wherein the substituents at positions "2" and “3" of the nitrogen containing ring are in the cis configuration, R 9 is benzhydryl and A is phenyl; or (b) R 3 is a group of the formula VII wherein R 12 and the substituent at position "3" of the nitrogen containing ring are in the cis configuration, A is phenyl, R 12 is phenyl, each of R 2 , R 13 , R 14 , R 15 and R 16 is hydrogen, m is zero, W is methoxy or isopropoxy, X is -(CH 2 ) 3 - and R 1 is thiazolyl, imidazolyl, pyrrolyl, oxazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiophenyl or thiadiazolyl.
- R 3 is a group of the formula IX wherein the substituents at positions "2" and “3" of the nitrogen containing ring are in the cis configuration, R 19 is benzhydryl, r is two and the fused bicyclic ring system to which W and the -CH 2 NR 2 R 3 sidechain are attached is benzisoxazolyl or benzthiazolyl.
- Especially preferred compounds of the formula lb are those wherein R 3 is a group of the formula IX, R 19 is benzhydryl, the fused bicyclic ring system to which W and the -CH 2 NR 2 R 3 sidechain are attached is benzisoxazolyl, and W is methoxy.
- R 3 is a group of the formula VII
- R 12 is phenyl
- each of R 13 , R 14 , R 15 and R 16 is hydrogen
- m is zero
- X is -(CH 2 ) 3 -
- the fused bicyclic ring system to which W and the -CH 2 NR 2 R 3 sidechain are attached is benzothiazolyl, benzoxazolyl, benzthiophenyl or benzimidazolyl.
- R 3 is a group of the formula VII
- each of R 13 , R 14 , R 15 and R 16 is hydrogen
- m is zero
- X is -(CH 2 ) 3 -
- A is phenyl
- W is methoxy
- R 1 is selected from thiazolyl, imidazolyl, thiadiazolyl, pyridyl, pyrimidinyl, pyrazolyl, thiophenyl and isoxazolyl.
- the present invention also relates to compounds of the formulae
- X' is -S- or -O-
- R 22 is methyl, ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, (C 1 -C 6 ) alkyl, (C 3 -C 6 ) cycloalkyl or benzyl.
- the present invention also relates to a pharmaceutical composition for treating or preventing a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depression or dysthymic disorders, urinary incontinence, gastrointestinal disorders such as emesis and colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina, migraine and Reynaud's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders such as Alzheimer's disease, AIDS related dementia, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus
- the present invention also relates to a method of treating or preventing a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depression or dysthymic disorders, urinary incontinence, gastrointestinal disorders such as emesis and colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina, migraine and Reynaud's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders such as Alzheimer's disease, AIDS related dementia, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus
- the present invention also relates to a pharmaceutical composition for antagonizing the effects of substance P in a mammal, including a human, comprising a substance P antagonizing amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- the present invention also relates to a method of antagonizing the effects of substance P in a mammal, including a human, comprising administering to said mammal a substance P antagonizing amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof.
- the present invention also relates to a pharmaceutical composition for treating or preventing a disorder in a mammal, including a human, resulting from an excess of substance P, comprising a substance P antagonizing amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
- the present invention also relates to a method of treating or preventing a disorder in a mammal, including a human, resulting from an excess of substance P, comprising administering to said mammal a substance P antagonizing amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof.
- the present invention also relates to a pharmaceutical composition for treating or preventing a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depression or dysthymic disorders, urinary incontinence, gastrointestinal disorders such as emesis and colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina, migraine and Reynaud's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders such as Alzheimer's disease, AIDS related dementia, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus
- the present invention also relates to a method of treating or preventing a condition selected from the group consisting of inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depression or dysthymic disorders, urinary incontinence, gastrointestinal disorders such as emesis and colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina, migraine and Reynaud's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders such as Alzheimer's disease, AIDS related dementia, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus
- the present invention also relates to a pharmaceutical composition for treating or preventing a disorder in a mammal, including a human, the treatment or prevention of which is effected or facilitated by a decrease in substance P mediated neurotransmission, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in antagonizing the effect of substance P at its receptor site, and a pharmaceutically acceptable carrier.
- the present invention also relates to a method of treating or preventing a disorder in mammal, including a human, the treatment or prevention of which is effected or facilitated by a decrease in substance P mediated neurotransmission, comprising administering to said mammal an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in antagonizing the effect of substance P at its receptor site.
- the present invention also relates to a pharmaceutical composition for treating or preventing a disorder in a mammal, including a human, the treatment or prevention of which is effected or facilitated by a decrease in substance P mediated neurotransmission, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such disorder, and a pharmaceutically acceptable carrier.
- the present invention also relates to a method of treating or preventing a disorder in mammal, including a human, the treatment or prevention of which is effected or facilitated by a decrease in substance P mediated neurotransmission, comprising administering to said mammal an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such disorder.
- the compounds of the formula I have chiral centers and therefore exist in different enantiomeric forms.
- This invention relates to all optical isomers and all stereoisomers of compounds of the formula I, and mixtures thereof.
- Scheme 1 illustrates the preparation of compounds of the formula Ia from starting materials of the formula X wherein G is hydrogen, hydroxy, chloro, bromo or (C 1 - C 6 ) alkoxy.
- a compound of the formula X wherein G is hydrogen may be converted directly into the corresponding compound of the formula I by reacting it with a compound of the formula NH 2 R 3 in the presence of a reducing agent.
- Reducing agents that may be used include sodium cyanoborohydride, sodium triacetoxyborohydride, sodium borohydride, hydrogen and a metal catalyst, zinc and hydrochloric acid, and formic acid. This reaction is typically conducted in a reaction inert solvent at a temperature from about 0°C to about 150°C.
- Suitable reaction inert solvents include lower alcohols (e.g., methanol, ethanol and isopropanol), 1,2-dichloroethane, acetic acid and tetrahydrofuran (THF).
- the solvent is acetic acid
- the temperature is about 25°C
- the reducing agent is sodium triacetoxyborohydride
- the reaction is conducted in the presence of a dehydrating agent such as molecular sieves.
- reaction of a compound of the formula X with a compound of the formula NH 2 R 3 may be carried out in the presence of a dehydrating agent or by using an apparatus designed to remove azeotropically the water generated, to produce an imine of the formula
- the preparation of the imine XI is generally carried out in a reaction inert solvent such as benzene, xylene or toluene, preferably toluene, at a temperature from about 25°C to about 110°C, preferably at about the reflux temperature of the solvent.
- Suitable dehydrating agents/ solvent systems include titanium tetrachloride/ dichloromethane, titanium isopropoxide/dichloromethane and molecular sieves. Titanium tetrachloride/dichloromethane is preferred.
- activating agents include carbonyldiimidazole, chloroformates such as isobutyl chloroformate, diethylphosphoryl cyanide and dicyclohexylcarbodiimide. Carbonyldiimidazole is preferred. This reaction is generally conducted at a temperature from about 0°C to about 50°C, preferably at about 25°C, in an inert solvent such as chloroform, diethyl ether, THF or dimethylformamide (DMF).
- chloroformates such as isobutyl chloroformate
- diethylphosphoryl cyanide diethylphosphoryl cyanide
- dicyclohexylcarbodiimide dicyclohexylcarbodiimide.
- Carbonyldiimidazole is preferred. This reaction is generally conducted at a temperature from about 0°C to about 50°C, preferably at about 25°C, in an inert solvent such as chloroform, diethyl ether, THF
- the reaction of the compound of formula X with the appropriate compound of formula NH 2 R 3 is typically carried out in the presence of an acid scavenger in an aprotic solvent at a temperature from about 0°C to about 100°C.
- Suitable acid scavengers include triethylamine (TEA), pyridine and inorganic salts such as sodium and potassium carbonate.
- Suitable solvents include methylene chloride (CH 2 Cl 2 ), chloroform (CHCl 3 ), benzene, toluene and tetrahydrofuran (THF).
- the reaction is conducted in CH 2 Cl 2 at room temperature using TEA as the acid scavenger.
- the reaction of the compound of formula NH 2 R 3 is usually conducted in an aprotic solvent such as benzene, toluene, chlorobenzene or xylenes, at a temperature from about 25°C to about 100°C, preferably at about the reflux temperature of the solvent.
- an aprotic solvent such as benzene, toluene, chlorobenzene or xylenes
- Reduction of the compound of formula XII so formed yields the corresponding compound of the formula I wherein R 2 is hydrogen.
- a reducing agent such as lithium aluminum hydride, borane dimethylsulfide complex, borane-THF or diborane
- an aprotic solvent such as THF, dioxane or diethyl ether
- the reducing agent is borane dimethylsulfide complex and the reaction is carried out at about room temperature in an ethereal solvent such as THF.
- R 2 is hydrogen
- R 2 is -CO 2 (C 1 -C 10 ) alkyl by reacting them with a (C 1 -C 10 ) alkyl halo- carbonate such as methyl or ethyl chloroformate in the presence of an acid scavenger.
- this reaction is conducted in an polar solvent such as chloroform, methylene chloride, water or a water/acetone mixture, at a temperature from about 0°C to about 100°C, preferably at about room temperature.
- Suitable acid scavengers include triethylamine, pyridine and potassium and sodium carbonate or bicarbonate.
- the starting materials of the formula NH 2 R 3 may be prepared as described in United States Patent 5,162,339, which issued on November 11, 1992. This patent is incorporated herein in its entirety.
- the starting materials of the formula NH 2 R 3 may be prepared as described in United States Patent Application Serial No. 532,525, filed June 1 , 1990 and PCT Patent Application PCT/US 91/02853, filed April 25, 1991. Both these applications are incorporated herein in their entirety.
- R 3 is a group of the formula IV, V or VI
- the starting materials of the formula NH 2 R 3 may be prepared as described in United States Patent Application Serial No. 557,442, filed July 23, 1990 and PCT Patent Application PCT/US 91/03369, filed May 14, 1991. Both these applications are incorporated herein in their entirety.
- R 3 is a group of the formula VII
- the starting materials of the formula NH 2 R 3 may be prepared as described in United States Patent Application Serial No. 724,268, filed July 1, 1991, United States Patent Application Serial No. 800,667, filed November 27, 1991 and PCT Patent Application PCT/US 92/00065, filed January 14, 1992. These applications are incorporated herein in their entirety.
- R 3 is a group of the formula VIII
- the starting materials of the formula NH 2 R 3 may be prepared as described in PCT Patent Application PCT/US 91/05776, filed August 20, 1991, United States Patent Application Serial No. 800,667, filed November 27, 1991 and PCT Patent Application PCT/US 92/00065, filed January 14, 1992. These applications are incorporated herein in their entirety.
- R 3 is a group of the formula IX
- the starting materials of the formula NH 2 R 3 may be prepared as described in United States Patent Application Serial No. 719,884, filed June 21, 1991. This application is incorporated herein in its entirety.
- Scheme 2 illustrates one method of preparing the starting materials of formula X wherein G is hydrogen. This is the preferred method of preparing compounds of the formula X wherein G is hydrogen and R 1 is thiazolyl, thiadiazolyl and oxazolyl. Once formed, these compounds can be converted into the corresponding compounds of the formula I or XI according to the procedures described above.
- a compound of the formula XIII is reacted with titanium tetrachloride (TiCl 4 ) or tin tetrachloride (SnCl 4 ) and dichloromethyl methyl ether (CHC1 2 - O-CH 3 ) at a temperature from about 0°C to about room temperature, preferably at about 0°C, in a methylene chloride or tetrachloroethylene solvent to yield the corresponding aldehyde of formula X wherein G is hydrogen.
- TiCl 4 titanium tetrachloride
- SnCl 4 tin tetrachloride
- CHC1 2 - O-CH 3 dichloromethyl methyl ether
- the compound of the formula XIII may be reacted with hexamethylene tetraamine and trifluoroacetic acid at a temperature from about 25°C to about 80°C, preferably at about 70°C, to yield the same product.
- Scheme 3 illustrates a preferred method of preparing compounds of the formula X wherein G is hydrogen and R 1 is a nitrogen containing heterocyclic group (e.g., a pyrrolyl, triazolyl or imidazolyl group).
- G is hydrogen and R 1 is a nitrogen containing heterocyclic group (e.g., a pyrrolyl, triazolyl or imidazolyl group).
- -CHO group of a benzaldehyde of the formula XIV is protected by conversion to the corresponding 1,3-dioxolane of formula XV, wherein R 5 is a suitable leaving group such as iodine or bromine.
- This reaction is generally carried out by heating a mixture of the benzaldehyde and ethylene glycol in an inert solvent such as benzene or toluene, preferably in the presence of an acid catalyst such as p-toluenesulfonic acid, and preferably at the reflux temperature of the solvent to remove the water formed in the reaction.
- the resulting compound of formula XV is then reacted with a heterocyclic compound of the formula R*H to form the corresponding compound of formula XVI.
- the reaction is carried out in an aprotic, nonpolar solvent such as xylene or toluene, or in the absence of a solvent (e.g., as a melt of imidazole and the compound of the formula XV) at a temperature from about 100°C to about 300°C, in the presence of an inorganic metal catalyst such as copper metal or copper iodide, in a high pressure reactor at a pressure from about 1 atm to about 5 atm.
- the reaction is carried out neat using a copper metal catalyst, at a temperature from about 140°C to about 160°C and at a pressure from about 2 atm to about 3 atm.
- compounds of the formula X wherein G is hydrogen and R 1 does not contain an ionizable proton can be prepared by reacting a compound of the formula XV, as depicted in scheme 3 and defined above, wherein R 5 is bromine or iodine, with magnesium metal to form a Grignard reagent of the formula
- R 20 is methyl with potassium permanganate in a reaction inert solvent such as acetone; (2) oxidizing an alcohol of the formula XVII wherein R 20 is hydroxymethyl with manganese dioxide; or (3) subjecting a compound of the formula XVII wherein R 20 is chloro, bromo or iodo to Grignard reaction conditions (i.e., reacting the compound of formula XVII with magnesium metal to form an intermediate of the formula
- Carboxylic esters of the formula X wherein G is (C 1 - C 6 ) alkoxy can be prepared by a variety of methods known in the art.
- One such method involves reacting the corresponding acid halide in a (C 1 -C 6 ) alkanol in the presence of a catalytic amount of hydrochloric, sulfuric or para- toluenesulfonic acid at a temperature from about room temperature to about the boiling point of the alcohol employed.
- Compounds of the formula Ia wherein R 1 is pyrrolyl can also be prepared from the corresponding compounds wherein R 1 is replaced by an amino group.
- the corresponding amine may be obtained by reducing the corresponding nitro compound using one of several methods known to those skilled in the art.
- One such method involves catalytic hydrogenation of the nitro compound using hydrogen gas and a palladium on carbon catalyst in an inert solvent such as methanol or ethanol at about room temperature and a pressure of about 1- 5 atm.
- the reduction can also be accomplished using a reducing agent such as borane/methyl sulfide in tetrahydrofuran at a temperature from about 25°C to about 70°C, preferably at the reflux temperature of the solvent.
- a reducing agent such as borane/methyl sulfide in tetrahydrofuran at a temperature from about 25°C to about 70°C, preferably at the reflux temperature of the solvent.
- Scheme 4 illustrates a method of preparing compounds of the formula
- R 22 is methyl, ethyl, n-propyl, isopropyl, t-butyl, trifluoromethyl, (C 1 -C 6 ) alkyl or benzyl
- R 23 is methyl, ethyl, propyl, isopropyl, t-butyl, trifluoromethyl, (C 1 - C 6 ) alkyl, benzyl or phenyl optionally substituted with from one to three substituents independently selected from halo, trifluoromethoxy, (C 1 -C 6 ) alkyl and (C 1 -C 6 ) alkoxy.
- Such compounds of the formula lb may be prepared from the foregoing aldehydes of formula XVIII as described above and depicted in scheme 1.
- compounds of the formula XX may be prepared by direct alkylation of the corresponding phenols of the formula XIX using a common alkylating agent such as dimethyl sulfate, a methyl halide (e.g., methyl iodide), methyl triflate, methyl mesylate or methyl tosylate.
- a common alkylating agent such as dimethyl sulfate, a methyl halide (e.g., methyl iodide), methyl triflate, methyl mesylate or methyl tosylate.
- the reaction is usually conducted in an inert solvent such as dimethyl formamide, N-methyl pyrrolidinone, tetrahydrofuran, methylene chloride or another similar solvent for a period of about 0.5 to 12 hours at a temperature of about 0°C to the reflux temperature of the solvent.
- a base such as sodium hydride or potassium hydride is used, but other bases such as triethylamine, 1,8-diazobicyclo[5.4.0]undec-7-ene may be utilized as well.
- the carboxylic acid functionality of the phenol of formula XIX is also alkylated.
- various esterified derivatives of the compounds of formula XIX such as the methyl or ethyl ester (not shown in scheme 4) are also suitable starting materials for the foregoing transformation.
- Reduction of the nitro functionality in the resulting compound of formula XX to yield the corresponding amine of formula XXI may be effected through hydrogenation with a noble metal catalyst such as platinum or palladium under a pressure of about 1-100 atmospheres of hydrogen gas in an inert solvent such as methanol, ethanol, ether, tetrahydrofuran or water (or a mixture of two or more such solvents).
- a noble metal catalyst such as platinum or palladium under a pressure of about 1-100 atmospheres of hydrogen gas in an inert solvent such as methanol, ethanol, ether, tetrahydrofuran or water (or a mixture of two or more such solvents).
- the reaction is most conveniently run at ambient temperature for about 0.5 to 12 hours.
- reduction of the nitro functionality may be carried out using a metal such as zinc or tin in a solvent such as acetic acid or water.
- Formation of the amide of formula XXII is most conveniently conducted in an inert solvent such as methylene chloride, dichloroethane, tetrahydrofuran or toluene using one or more equivalents of an acylating agent such as acetic anhydride, acetyl chloride, benzoyl chloride, trimethylacetyl chloride, cyclopropyl carbonyl chloride or another alkyl or aryl acid chloride or anhydride.
- the reaction is most conveniently carried out in the presence of a base such as triethylamine or diisopropylamine or in aqueous solution under Schotten-Baumann conditions with sodium hydroxide.
- the reaction is generally conducted between about 0°C and 60°C, with room temperature being preferred.
- the thioamide of formula XXIII is formed from the corresponding amide of formula XXII by reacting the latter compound with a reagent such as 2,4-bis(4-methoxyphenyl)- 1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent) or phosphorous pentasulfide in an inert solvent such as toluene, benzene, dichloroethane, dimethylformamide or hexamethylphosphorous triamide at a temperature from about room temperature to the reflux point of the solvent.
- a reagent such as 2,4-bis(4-methoxyphenyl)- 1,3-dithia-2,4-diphosphetane-2,4-disulfide (Lawesson's Reagent) or phosphorous pentasulfide in an inert solvent such as toluene, benzene, dichlor
- Cyclization of the thioamide of formula XXIII to form a mixture of regioisomeric benzothiazoles of the formulae XXIV and XXV is carried out by reacting the substrate with potassium ferricyanide in an aqueous base heated to about 50°C for a period of about 1 to 12 hours.
- the mixture of regioisomers may be separated at this point or carried through to the end of the synthetic sequence.
- Reduction of the mixture of compounds of the formulae XXIV and XXV or of the compound of formula XXIV alone can be conducted using a reducing agent such as lithium aluminum hydride, borane-THF, sodium bismethoxyethylaluminum hydride or a similar reducing agent in an inert solvent such as ether, tetrahydrofuran, dimethoxyethane or toluene.
- a reducing agent such as lithium aluminum hydride, borane-THF, sodium bismethoxyethylaluminum hydride or a similar reducing agent in an inert solvent such as ether, tetrahydrofuran, dimethoxyethane or toluene.
- the reaction may be carried out at a temperature between about 0°C and room temperature for a period of about 1 to 12 hours.
- the resulting mixture of the regioisomeric alcohols of the formulae XXVI and XXVII may be oxidized to form the desired aldehyde of formula XXVIII by reacting it with manganese dioxide in refluxing methylisobutyl ketone or another inert solvent for a period of about 1-12 hours.
- the oxidation can be carried out under "Swern" conditions (i.e., a mixture of dimethyl sulfoxide in methylene chloride with activation by oxalyl chloride or trifluoroacetic anhydride) or using other methods well known to those familiar with the art.
- oxidizing agents such as pyridinium chlorochromate and pyridinium dichromate in an inert solvent such as methylene chloride, chloroform or dichloroethane.
- pressure is not critical unless otherwise indicated. Pressures from about 0.5 atmospheres to about 5 atmospheres are generally acceptable, and ambient pressure, i.e. about 1 atmosphere, is preferred as a matter of convenience.
- novel compounds of the formula I and the pharmaceutically acceptable salts thereof are useful as substance P antagonists, i.e., they possess the ability to antagonize the effects of substance P at its receptor site in mammals, and therefore they are able to function as therapeutic agents in the treatment of the aforementioned disorders and diseases in an afflicted mammal.
- the compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the Formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent and subsequently convert the latter free base to a pharmaceutically acceptable acid addition salt.
- the acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent, such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is readily obtained.
- Those compounds of the formula I which are also acidic in nature, e.g., where R 6 or R 10 is carboxyphenyl, are capable of forming base salts with various pharmacologically acceptable cations.
- Such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques.
- the chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the acidic compounds of formula I.
- Such non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc.
- salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure.
- they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before.
- stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum yields of the desired final product.
- the compounds of formula I and their pharmaceutically acceptable salts exhibit substance P receptor-binding activity and therefore are of value in the treatment and prevention of a wide variety of clinical conditions the treatment or prevention of which are effected or facilitated by a decrease in substance P mediated neurotransmission.
- Such conditions include inflammatory diseases (e.g., arthritis, psoriasis, asthma and inflammatory bowel disease), anxiety, depression or dysthymic disorders, urinary incontinence, gastrointestinal disorders such as emesis and colitis, psychosis, pain, allergies such as eczema and rhinitis, chronic obstructive airways disease, hypersensitivity disorders such as poison ivy, vasospastic diseases such as angina, migraine and Reynaud's disease, fibrosing and collagen diseases such as scleroderma and eosinophilic fascioliasis, reflex sympathetic dystrophy such as shoulder/hand syndrome, addiction disorders such as alcoholism, stress related somatic disorders, peripheral neuropathy, neuralgia, neuropathological disorders such as Alzheimer's disease, AIDS related dementia, diabetic neuropathy and multiple sclerosis, disorders related to immune enhancement or suppression such as systemic lupus erythematosus, and rheumatic diseases such as fibrositis.
- the compounds of the formula I and the pharmaceutically acceptable salts thereof can be administered via either the oral, parenteral or topical routes.
- these compounds are most desirably administered in dosages ranging from about 5.0 mg up to about 1500 mg per day, although variations will necessarily occur depending upon the weight and condition of the subject being treated and the particular route of administration chosen.
- a dosage level that is in the range of about 0.07 mg to about 21 mg per kg of body weight per day is most desirably employed. Variations may nevertheless occur depending upon the species of animal being treated and its individual response to said medicament, as well as on the type of pharmaceutical formulation chosen and the time period and interval at which such administration is carried out.
- dosage levels below the lower limit of the aforesaid range may be more than adequate, while in other cases still larger doses may be employed without causing any harmful side effect, provided that such larger doses are first divided into several small doses for administration throughout the day.
- the compounds of the formula I and their pharmaceutically acceptable salts may be administered alone or in combination with pharmaceutically acceptable carriers or diluents by either of the three routes previously indicated, and such administration may be carried out in single or multiple doses.
- the novel therapeutic agents of this invention can be administered in a wide variety of different dosage forms, i.e., they may be combined with various pharmaceutically acceptable inert carriers in the form of tablets, capsules, lozenges, troches, hard candies, powders, sprays, creams, salves, suppositories, jellies, gels, pastes, lotions, ointments, aqueous suspensions, injectable solutions, elixirs, syrups, and the like.
- Such carriers include solid diluents or fillers, sterile aqueous media and various non-toxic organic solvents, etc.
- oral pharmaceutical compositions can be suitably sweetened and/or flavored.
- the therapeutic compounds of this invention are present in such dosage forms at concentration levels ranging from about 5.0% to about 70% by weight.
- tablets containing various excipients such as microcrystalline cellulose, sodium citrate, calcium carbonate, dicalcium phosphate and glycine may be employed along with various disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
- disintegrants such as starch (and preferably corn, potato or tapioca starch), alginic acid and certain complex silicates, together with granulation binders like polyvinylpyrrolidone, sucrose, gelatin and acacia.
- lubricating agents such as magnesium stearate, sodium lauryl sulfate and talc are often very useful for tabletting purposes.
- compositions of a similar type may also be employed as fillers in gelatin capsules; preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
- preferred materials in this connection also include lactose or milk sugar as well as high molecular weight polyethylene glycols.
- the active ingredient may be combined with various sweetening or flavoring agents, coloring matter or dyes, and, if so desired, emulsifying and/or suspending agents as well, together with such diluents as water, ethanol, propylene glycol, glycerin and various like combinations thereof.
- solutions of a therapeutic compound of the present invention in either sesame or peanut oil or in aqueous propylene glycol may be employed.
- the aqueous solutions should be suitably buffered if necessary and the liquid diluent first rendered isotonic.
- These aqueous solutions are suitable for intravenous injection purposes.
- the oily solutions are suitable for intraarticular, intramuscular and subcutaneous injection purposes. The preparation of all these solutions under sterile conditions is readily accomplished by standard pharmaceutical techniques well known to those skilled in the art.
- the therapeutic compounds of the present invention may be administered topically when treating inflammatory conditions of the skin and this may preferably be done by way of creams, jellies, gels, pastes, ointments and the like, in accordance with standard pharmaceutical practice.
- the activity of the therapeutic compounds of the present invention as substance P receptor antagonists may be determined by their ability to inhibit the binding of substance P at its receptor sites in bovine caudate tissue, employing radioactive ligands to visualize the tachykinin receptors by means of autoradiography.
- the substance P antagonizing activity of the herein described compounds may be evaluated by using the standard assay procedure described by M. A. Cascieri et al., as reported in the Journal of Biological Chemistry, Vol. 258, p. 5158 (1983). This method essentially involves determining the concentration of the individual compound required to reduce by 50% the amount of radiolabelled substance P ligands at their receptor sites in said isolated cow tissues, thereby affording characteristic IC 50 values for each compound tested.
- bovine caudate tissue is removed from a -70°C freezer and homogenized in 50 volumes (w./v.) of an ice-cold 50 mM Tris (i.e., trimethamine which is 2-amino-2-hydroxymethyl-1,3-propanediol) hydrochloride buffer having a pH of 7.7.
- Tris i.e., trimethamine which is 2-amino-2-hydroxymethyl-1,3-propanediol
- the homogenate is centrifuged at 30,000 x G for a period of 20 minutes.
- the pellet is resuspended in 50 volumes of Tris buffer, rehomogenized and then recentrifuged at 30,000 x G for another twenty- minute period.
- the pellet is then resuspended in 40 volumes of ice-cold 50 mM Tris buffer (pH 7.7) containing 2 mM of calcium chloride, 2 mM of magnesium chloride, 4 ⁇ g/ml of bacitracin, 4 ⁇ g/ml of leupeptin, 2 ⁇ g of chymostatin and 200 g/ml of bovine serum albumin. This step completes the production of the tissue preparation.
- the radioligand binding procedure is then carried out in the following manner, viz., by initiating the reaction via the addition of 100 ⁇ l of the test compound made up to a concentration of 1 ⁇ M, followed by the addition of
- Plasma extravasation is induced by intradermal administration of substance P (50 ⁇ l, 0.01% BSA-saline solution) in dorsal skin of pentobarbital (25 mg/kg i.p.) anesthetized male Hartley guinea pigs weighing 450-500 g.
- the compound to be tested is dissolved in 0.1% methyl cellulose-water (MC) and dosed p.o. 1 hour before substance P challenge (3 pmol/site).
- Evans blue dye (30 mg/kg) is administered intravenously 5 minutes before challenge. After 10 minutes, the animals are sacrificed, the dorsal skin is removed, and the blue spots are punched out using a cork borer (11.5 mm oral dose (o.d.)). Tissue dye content is quantitated after overnight formamide extraction at 600 nm absorbance.
- Plasma extravasation is induced by intraperitoneal injection of capsaicin (10 ml of 30 ⁇ M solution in 0.1% BSA/saline) into pentobarbital anesthetized (25 mg/kg i.p.) guinea pigs.
- capsaicin 10 ml of 30 ⁇ M solution in 0.1% BSA/saline
- pentobarbital anesthetized 25 mg/kg i.p.
- guinea pigs The compound to be tested is dissolved in 0.1% MC and dosed p.o. 1 hour before capsaicin challenge.
- Evans blue dye (30 mg/kg) is administered i.v. 5 minutes before challenge. After 10 minutes, the animals are sacrificed, and both right and left ureters are removed. Tissue dye content is quantitated as in "a" above.
- mice Male ddY mice (SLC, Japan), weighing 14-18 g, were fasted overnight.
- the compound to be tested is dissolved in 0.1% MC and dosed p.o. 0.5 hour before acetic acid (AA) injection (0.7%, 0.16 ml/10 g body weight).
- AA acetic acid
- the animals are placed in clear beakers (1 per beaker) and the stretching response is counted 10 to 20 minutes after the AA injection (10 minute interval).
- the anti-psychotic activity of the therapeutic compounds of the present invention as neuroleptic agents for the control of various psychotic disorders may be determined by a study of their ability to suppress substance P-induced or substance P agonist induced hypermotility in guinea pigs. This study is carried out by first dosing the guinea pigs with a control compound or with an appropriate test compound of the present invention, then injecting the guinea pigs with substance P or a substance P agonist by intracerebral administration via canula and thereafter measuring their individual locomotor response to said stimulus.
- 6-Methoxy-2-methyl-benzoxazole (1.06 grams, 6.5 mmol) was taken up in 65 mL of dry methylene chloride and cooled to 0°C. Titanium tetrachloride (10.11 grams, 53.3 mmol) was added via syringe and the deep red solution was stirred for 30 min. Dichloromethyl methyl ether (4.63 grams, 40.3 mmol) was added dropwise and the reaction mixture darkened to a brown color. The reaction mixture was allowed to warm to room temperature and was stirred for 18 hours. The mixture was quenched into ice and water. The slurry was basified with aqueous saturated bicarbonate and extracted with methylene chloride.
- 6-Methoxy-2-methyl-benzothiazole [3.34 grams (18.63 mmol)] was taken up in 35 mL of trifluoroacetic acid and treated with 2.62 grams (18.63 mmol) of hexamethylenetetramine. The reaction was heated under reflux for seven hours. The reaction mixture was allowed to cool and was evaporated in vacuo. The residue was diluted with 200 mL of ethyl acetate and treated with 100 mL of saturated sodium bicarbonate solution. The organic phase was washed with saturated brine solution and was dried and evaporated.
- 6-Methoxy-3-methyl-benzo[d]isoxazole (1.4 g, 8.58 mmol) was taken up in 200 mL of trifluoroacetic acid and treated with 1.20 grams (8.6 mmol) of hexamethylenetetramine. The reaction was heated under reflux for 24 hours. The reaction mixture was allowed to cool and was evaporated in vacuo. The residue was diluted with 200 mL of methylene chloride and treated with 200 mL of saturated sodium bicarbonate solution. The organic phase was washed with saturated brine solution and was dried and evaporated. The residue was chromatographed on silica gel (elution with 15% ethyl acetate in hexanes) to provide 122.6 mg of the desired aldehyde.
- the crude product was chromatographed on silica gel eluting with a mixture of methylene chloride, methanol and aqueous ammonium hydroxide (98:1:1) to afford 90 mg of free base.
- the dihydrochloride salt was formed after dissolution of the free base in ether and treatment with saturated HCl gas, also in ether.
- the crude salt was obtained by direct evaporation of this reaction mixture.
- the residue was taken up in methanol (1 mL), clarified and treated with ether until the cloud point. The mixture was stirred overnight, whereupon crystallization occurred. The resulting solid (35 mg) was isolated by filtration.
- IR dihydrochloride salt (neat) ⁇ 3000 (br), 2550 (br), 1620, 1580, 1500, 1480, 1460, 1440, 1380, 1350, 1310, 1210, 1150, 1120 cm -1 .
- IR dihydrochloride salt (neat) ⁇ 2700 br, 1610, 1560, 1520, 1460, 1430, 1420, 1280, 1220, 1050 cm -1 .
- the oil was converted to the hydrochloride salt of the title compound by suspending the free base in CH 2 Cl 2 and treating it with 257 ⁇ L of 4M HCl in dioxane (2 equivalents), stirring at 25°C for 20 min, filtering and drying the solid in vacuo to give a light yellow solid, 0.19 grams.
- a 500 ml round bottom flask was charged with 5.35 grams of 60% sodium hydride dispersion and the solid was washed twice with hexane and decanted (under nitrogen). The residue was suspended in 200 mL of dimethylformamide (DMF), cooled to 0°C and was treated with 11 grams (60 mmol) of 2- hydroxy-5-nitrobenzoic acid. The reaction mixture was stirred for 1 hour at 0°C. The mixture was then treated with 17 mL (180 mmol) dimethyl sulfate and was allowed to warm to room temperature while stirring for 1.5 hours. An additional 17 mL of dimethyl sulfate was added and the reaction was stirred overnight at room temperature.
- DMF dimethylformamide
- the mixture was diluted with 1.5 L ethyl acetate and was washed with 400 ml of 0.75 M aqueous sodium hydroxide (NaOH) solution followed by 400 mL of saturated bicarbonate solution, 400 mL of water and 500 mL of saturated brine.
- NaOH sodium hydroxide
- the organic phase was dried and evaporated. There was obtained 11.6 grams of the desired product as yellow flakes.
- the material was generally used without purification.
Abstract
Priority Applications (8)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
DK93922821T DK0675886T3 (da) | 1992-12-10 | 1993-10-07 | Aminomethylensubstituerede ikke-aromatiske heterocykler og deres anvendelse som substance P-antagonister |
AU51696/93A AU5169693A (en) | 1992-12-10 | 1993-10-07 | Aminomethylene substituted non-aromatic heterocycles and use as substance p antagonists |
DE69328975T DE69328975T2 (de) | 1992-12-10 | 1993-10-07 | Aminomethylen substituierte heterocyclische verbindungen und ihre verwendung alssubstanz p antagonisten |
AT93922821T ATE194340T1 (de) | 1992-12-10 | 1993-10-07 | Aminomethylen substituierte heterocyclische verbindungen und ihre verwendung alssubstanz p antagonisten |
CA002150123A CA2150123C (fr) | 1992-12-10 | 1993-10-07 | Derives de substitution aminomethylene d'heterocycles non aromatiques |
US08/522,230 US5854262A (en) | 1993-10-07 | 1993-10-07 | Aminomethylene substituted non-aromatic heterocycles and use as substance P antagonists |
EP93922821A EP0675886B1 (fr) | 1992-12-10 | 1993-10-07 | Heterocycles non aromatiques substitues par aminomethylene et leur utilisation comme antagonistes de substance p |
GR20000402017T GR3034329T3 (en) | 1992-12-10 | 2000-09-05 | Aminomethylene substituted non-aromatic heterocycles and use as substance p antagonists. |
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US98865392A | 1992-12-10 | 1992-12-10 | |
US07/988,653 | 1992-12-10 |
Related Parent Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US98865392A Continuation-In-Part | 1992-12-10 | 1992-12-10 |
Related Child Applications (2)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
US08/522,230 A-371-Of-International US5854262A (en) | 1993-10-07 | 1993-10-07 | Aminomethylene substituted non-aromatic heterocycles and use as substance P antagonists |
US16640298A Division | 1992-12-10 | 1998-10-05 |
Publications (1)
Publication Number | Publication Date |
---|---|
WO1994013663A1 true WO1994013663A1 (fr) | 1994-06-23 |
Family
ID=25534364
Family Applications (1)
Application Number | Title | Priority Date | Filing Date |
---|---|---|---|
PCT/US1993/009407 WO1994013663A1 (fr) | 1992-12-10 | 1993-10-07 | Heterocycles non aromatiques substitues par aminomethylene et leur utilisation comme antagonistes de substance p |
Country Status (15)
Country | Link |
---|---|
EP (2) | EP0806423A1 (fr) |
JP (2) | JP2722279B2 (fr) |
CN (1) | CN1092771A (fr) |
AT (1) | ATE194340T1 (fr) |
AU (1) | AU5169693A (fr) |
CA (1) | CA2150123C (fr) |
DE (1) | DE69328975T2 (fr) |
DK (1) | DK0675886T3 (fr) |
ES (1) | ES2147759T3 (fr) |
FI (1) | FI935529A (fr) |
GR (1) | GR3034329T3 (fr) |
IL (1) | IL107843A0 (fr) |
MX (1) | MX9307810A (fr) |
PT (1) | PT675886E (fr) |
WO (1) | WO1994013663A1 (fr) |
Cited By (62)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0627221A2 (fr) * | 1993-06-04 | 1994-12-07 | Pfizer Inc. | Antagonistes de la substance P pour le traitement du vomissement |
WO1995007908A1 (fr) * | 1993-09-17 | 1995-03-23 | Pfizer Inc. | 3-benzylaminomethyl-piperidines a substitution heteroarylamino et heteroarylsulfonamido, et composes apparentes |
EP0653208A2 (fr) * | 1993-11-17 | 1995-05-17 | Pfizer Inc. | Antagonistes de la substance P pour le traitement et la prévention de l'erythème solaire |
EP0655246A1 (fr) * | 1993-11-30 | 1995-05-31 | Pfizer Inc. | Antagonistes de la substance P pour le traitement des maladies causées par Helicobacter Pylori ou d'autres bacteries spirales, ureare-positives, gram-négatives |
EP0659409A2 (fr) * | 1993-11-23 | 1995-06-28 | Pfizer Inc. | Antagonistes de la substance P pour l'inhibition de l'angiogénése |
WO1996029326A1 (fr) * | 1995-03-21 | 1996-09-26 | Glaxo Group Limited | 3-benzylamino-2-phenylpiperidines en tant qu'antagonistes de neurokinine |
WO1996030367A1 (fr) * | 1995-03-27 | 1996-10-03 | Hisamitsu Pharmaceutical Co., Inc. | Derives de piperidine |
WO1997003066A1 (fr) * | 1995-07-07 | 1997-01-30 | Pfizer Pharmaceuticals Inc. | Composes de benzolactam substitues utilises comme antagonistes de la substance p |
EP0769300A2 (fr) | 1995-10-20 | 1997-04-23 | Pfizer Inc. | Médicament antiémétique contenant des Antagonistes des récepteurs NK-1 |
US5703240A (en) * | 1993-09-22 | 1997-12-30 | Glaxo Group Limited | Piperidine derivatives |
WO2000068224A1 (fr) * | 1999-05-06 | 2000-11-16 | Pfizer Products Inc. | Composes de benzolactame substitues |
EP1080080A4 (fr) * | 1998-06-08 | 2001-03-07 | Advanced Medicine Inc | Nouveaux agents therapeutiques modulant les recepteurs de neurokinines |
EP1095655A2 (fr) * | 1999-10-25 | 2001-05-02 | Pfizer Products Inc. | Recepteurs antagonistes NK-1 et eletriptan pour le traitement de la migraine |
US6288225B1 (en) | 1996-05-09 | 2001-09-11 | Pfizer Inc | Substituted benzolactam compounds as substance P antagonists |
WO2001079153A1 (fr) * | 2000-04-19 | 2001-10-25 | Neurotech Co., Ltd. | Composes, compositions et procedes de prevention de la neurodegenerescence dans des atteintes lesionnelles aigues et chroniques au systeme nerveux central |
EP1186318A2 (fr) * | 2000-09-06 | 2002-03-13 | Pfizer Products Inc. | Composition pour le traitement de la dépression et de l'anxieté contenant un antagoniste des recepteurs de 5HT 1 et un antagoniste du récepteur NK-1 |
EP1192952A2 (fr) * | 2000-09-28 | 2002-04-03 | Pfizer Products Inc. | Composition pour le traitement de la dépression et de l'anxieté contenant un antagoniste du recepteur NK-3 et un antagoniste du récepteur NK-1 |
WO2002028853A1 (fr) * | 2000-10-02 | 2002-04-11 | Tanabe Seiyaku Co., Ltd. | Compose de benzylamine, son procede de production et produit intermediaire correspondant |
US6573402B1 (en) | 2000-04-20 | 2003-06-03 | Neurotech Co., Ltd. | Compounds, compositions and methods for preventing neurodegeneration in acute and chronic injuries in the central nervous system |
US7119207B2 (en) * | 2000-04-10 | 2006-10-10 | Pfizer Inc | Benzoamide piperidine containing compounds and related compounds |
WO2006123182A2 (fr) | 2005-05-17 | 2006-11-23 | Merck Sharp & Dohme Limited | Sulfones de cyclohexyle pour le traitement du cancer |
WO2007011820A2 (fr) | 2005-07-15 | 2007-01-25 | Amr Technology, Inc. | Tetrahydrobenzazepines substituees par aryle et heteroaryle, et leur utilisation pour bloquer la reabsorption de la noradrenaline, de la dopamine, et de la serotonine |
US7186745B2 (en) | 2001-03-06 | 2007-03-06 | Astrazeneca Ab | Indolone derivatives having vascular damaging activity |
US7189878B2 (en) | 2002-06-19 | 2007-03-13 | Neurotech Co., Ltd. | Tetrafluorobenzyl derivatives and pharmaceutical composition for preventing and treating acute and chronic neurodegenerative diseases in central nervous system containing the same |
WO2007041052A2 (fr) | 2005-09-29 | 2007-04-12 | Merck & Co., Inc. | Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4 |
WO2007093827A1 (fr) | 2006-02-15 | 2007-08-23 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Dérivés de trifluoroéthanone substitués par thiophène et thiazole en tant qu'inhibiteurs d'histone désacétylase (hdac) |
WO2008120653A1 (fr) | 2007-04-02 | 2008-10-09 | Banyu Pharmaceutical Co., Ltd. | Dérivé d'indoledione |
WO2009002495A1 (fr) | 2007-06-27 | 2008-12-31 | Merck & Co., Inc. | Dérivés de 4-carboxybenzylamino utilisés en tant qu'inhibiteurs de l'histone désacétylase |
WO2009111354A2 (fr) | 2008-03-03 | 2009-09-11 | Tiger Pharmatech | Inhibiteurs de la tyrosine kinase |
WO2010114780A1 (fr) | 2009-04-01 | 2010-10-07 | Merck Sharp & Dohme Corp. | Inhibiteurs de l'activité akt |
WO2010132487A1 (fr) | 2009-05-12 | 2010-11-18 | Bristol-Myers Squibb Company | Formes cristallines de (s)-7-([1,2,4]triazolo[1,5-a] pyridin -6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline et leurs utilisations |
WO2010132442A1 (fr) | 2009-05-12 | 2010-11-18 | Albany Molecular Reserch, Inc. | 7-([1,2, 4,]triazolo[1,5,-a]pyridine-6-yl)-4-(3,4-dichlorophényl)-1,2,3,4- tétrahydroisoquinoline et son utilisation |
WO2010090494A3 (fr) * | 2009-02-09 | 2011-01-06 | 주식회사 뉴로테크 | Utilisation médicale de dérivés d'acide 5-benzylaminosalicylique ou de sels correspondants |
WO2011046771A1 (fr) | 2009-10-14 | 2011-04-21 | Schering Corporation | Pipéridines substituées qui accroissent l'activité de p53, et utilisations de ces composés |
EP2336120A1 (fr) | 2007-01-10 | 2011-06-22 | Istituto di ricerche di Biologia Molecolare P. Angeletti S.R.L. | Combinaisons contenant indazoles à substitution amide utilisés comme inhibiteurs de la poly(ADP-ribose)polymérase (PARP) |
WO2011163330A1 (fr) | 2010-06-24 | 2011-12-29 | Merck Sharp & Dohme Corp. | Nouveaux composés hétérocycliques utilisés comme inhibiteurs de erk |
WO2012018754A2 (fr) | 2010-08-02 | 2012-02-09 | Merck Sharp & Dohme Corp. | Inhibition à médiation par interférence arn de caténine (protéine associée à cadhérine), expression du gène bêta 1 (ctnnb1) à l'aide de petit acide nucléique interférent (sian) |
WO2012027236A1 (fr) | 2010-08-23 | 2012-03-01 | Schering Corporation | Nouveaux dérivés de pyrazolo[1,5-a]pyrimidine utilisés comme inhibiteurs de mtor |
WO2012030685A2 (fr) | 2010-09-01 | 2012-03-08 | Schering Corporation | Dérivés d'indazole utilisables en tant qu'inhibiteurs de la voie erk |
WO2012036997A1 (fr) | 2010-09-16 | 2012-03-22 | Schering Corporation | Dérivés condensés de pyrazole utilisés comme nouveaux inhibiteurs erk |
WO2012087772A1 (fr) | 2010-12-21 | 2012-06-28 | Schering Corporation | Dérivés d'indazole utiles en tant qu'inhibiteurs de erk |
WO2012145471A1 (fr) | 2011-04-21 | 2012-10-26 | Merck Sharp & Dohme Corp. | Inhibiteurs du récepteur du facteur de croissance 1 analogue à l'insuline |
WO2013063214A1 (fr) | 2011-10-27 | 2013-05-02 | Merck Sharp & Dohme Corp. | Nouveaux composés qui sont des inhibiteurs d'erk |
US8455470B2 (en) | 2006-04-13 | 2013-06-04 | Neurotech Pharmaceuticals Co., Ltd | Pharmaceutical composition for treating or preventing degenerative and inflammatory diseases |
WO2013165816A2 (fr) | 2012-05-02 | 2013-11-07 | Merck Sharp & Dohme Corp. | Compositions de petit acide nucléique interférent (sina) |
EP2698157A1 (fr) | 2006-09-22 | 2014-02-19 | Merck Sharp & Dohme Corp. | Procédé de traitement utilisant des inhibiteurs de synthèse d'acide gras |
US8686185B2 (en) | 2007-11-12 | 2014-04-01 | Neurotech Pharmaceuticals Co., Ltd. | Manufacturing method of 2-hydroxy-5-phenylalkylaminobenzoic acid derivatives and their salts |
WO2014052563A2 (fr) | 2012-09-28 | 2014-04-03 | Merck Sharp & Dohme Corp. | Nouveaux composés inhibiteurs de erk |
WO2014085216A1 (fr) | 2012-11-28 | 2014-06-05 | Merck Sharp & Dohme Corp. | Compositions et procédés pour traiter le cancer |
WO2014100065A1 (fr) | 2012-12-20 | 2014-06-26 | Merck Sharp & Dohme Corp. | Imidazopyridines substituées en tant qu'inhibiteurs de hdm2 |
WO2014120748A1 (fr) | 2013-01-30 | 2014-08-07 | Merck Sharp & Dohme Corp. | Purines 2,6,7,8-substituées utilisées en tant qu'inhibiteurs de hdm2 |
WO2015034925A1 (fr) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Polynucléotides circulaires |
US9034899B2 (en) | 2009-05-12 | 2015-05-19 | Albany Molecular Research, Inc. | Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof |
US9085531B2 (en) | 2004-07-15 | 2015-07-21 | Albany Molecular Research, Inc. | Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
US9156812B2 (en) | 2008-06-04 | 2015-10-13 | Bristol-Myers Squibb Company | Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine |
EP3327125A1 (fr) | 2010-10-29 | 2018-05-30 | Sirna Therapeutics, Inc. | Inhibition au moyen d'interférence arn d'une expression de gène utilisant des acides nucléiques à petit interférent (sina) |
WO2019094311A1 (fr) | 2017-11-08 | 2019-05-16 | Merck Sharp & Dohme Corp. | Inhibiteurs de prmt5 |
WO2020033282A1 (fr) | 2018-08-07 | 2020-02-13 | Merck Sharp & Dohme Corp. | Inhibiteurs de prmt5 |
WO2020033284A1 (fr) | 2018-08-07 | 2020-02-13 | Merck Sharp & Dohme Corp. | Inhibiteurs de prmt5 |
WO2020136441A1 (fr) * | 2018-12-28 | 2020-07-02 | Gnt Pharma Co., Ltd. | Compositions et méthodes de traitement de troubles neurodégénératifs |
US11096950B2 (en) | 2006-11-01 | 2021-08-24 | Barbara Brooke Jennings | Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development |
EP4079856A1 (fr) | 2010-08-17 | 2022-10-26 | Sirna Therapeutics, Inc. | Inhibition médiée par des arn interférents de l'expression génique du virus de l'hépatite b (vhb) à l'aide de petits acides nucléiques interférents (pani) |
Families Citing this family (2)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
US10154988B2 (en) | 2012-11-14 | 2018-12-18 | The Johns Hopkins University | Methods and compositions for treating schizophrenia |
CN109174181B (zh) * | 2018-08-10 | 2021-05-25 | 华东师范大学 | 一种负载双功能离子液体介孔聚合物的制备及其应用 |
Citations (10)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1990005525A1 (fr) * | 1988-11-23 | 1990-05-31 | Pfizer Inc. | Derives de quinuclidine en tant qu'antagonsites de substance p |
WO1991009844A1 (fr) * | 1990-01-04 | 1991-07-11 | Pfizer Inc. | Antagonistes de la substance p |
WO1991018878A1 (fr) * | 1990-05-31 | 1991-12-12 | Pfizer Inc. | Preparation de piperidines substituees |
WO1992001688A1 (fr) * | 1990-07-23 | 1992-02-06 | Pfizer Inc. | Derives de quinuclidine |
WO1992006079A1 (fr) * | 1990-09-28 | 1992-04-16 | Pfizer Inc. | Analogues cycliques d'heterocycles non aromatiques contenant de l'azote |
EP0499313A1 (fr) * | 1991-02-11 | 1992-08-19 | MERCK SHARP & DOHME LTD. | Composés azabicycliques, compositions pharmaceutiques les contenant et leur utilisation thérapeutique |
WO1992017449A1 (fr) * | 1991-03-26 | 1992-10-15 | Pfizer Inc. | Preparation stereoselective de piperidines substituees |
WO1992020676A1 (fr) * | 1991-05-22 | 1992-11-26 | Pfizer Inc. | 3-aminoquinuclidines substituees |
WO1993000330A2 (fr) * | 1991-06-21 | 1993-01-07 | Pfizer Inc. | Derives d'azanorbornane |
WO1993001170A1 (fr) * | 1991-07-01 | 1993-01-21 | Pfizer Inc. | Derives de 3-aminopiperidine et heterocycles associes contenant de l'azote |
-
1993
- 1993-10-07 AT AT93922821T patent/ATE194340T1/de not_active IP Right Cessation
- 1993-10-07 CA CA002150123A patent/CA2150123C/fr not_active Expired - Fee Related
- 1993-10-07 EP EP97202174A patent/EP0806423A1/fr not_active Withdrawn
- 1993-10-07 WO PCT/US1993/009407 patent/WO1994013663A1/fr active IP Right Grant
- 1993-10-07 DE DE69328975T patent/DE69328975T2/de not_active Expired - Fee Related
- 1993-10-07 EP EP93922821A patent/EP0675886B1/fr not_active Expired - Lifetime
- 1993-10-07 JP JP6514136A patent/JP2722279B2/ja not_active Expired - Fee Related
- 1993-10-07 ES ES93922821T patent/ES2147759T3/es not_active Expired - Lifetime
- 1993-10-07 DK DK93922821T patent/DK0675886T3/da active
- 1993-10-07 PT PT93922821T patent/PT675886E/pt unknown
- 1993-10-07 AU AU51696/93A patent/AU5169693A/en not_active Abandoned
- 1993-12-02 IL IL10784393A patent/IL107843A0/xx unknown
- 1993-12-09 MX MX9307810A patent/MX9307810A/es unknown
- 1993-12-09 FI FI935529A patent/FI935529A/fi unknown
- 1993-12-09 CN CN93120193A patent/CN1092771A/zh active Pending
-
1997
- 1997-08-22 JP JP24030897A patent/JP3165401B2/ja not_active Expired - Fee Related
-
2000
- 2000-09-05 GR GR20000402017T patent/GR3034329T3/el not_active IP Right Cessation
Patent Citations (11)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
WO1990005525A1 (fr) * | 1988-11-23 | 1990-05-31 | Pfizer Inc. | Derives de quinuclidine en tant qu'antagonsites de substance p |
WO1990005729A1 (fr) * | 1988-11-23 | 1990-05-31 | Pfizer Inc. | Agents therapeutiques de quinuclidine |
WO1991009844A1 (fr) * | 1990-01-04 | 1991-07-11 | Pfizer Inc. | Antagonistes de la substance p |
WO1991018878A1 (fr) * | 1990-05-31 | 1991-12-12 | Pfizer Inc. | Preparation de piperidines substituees |
WO1992001688A1 (fr) * | 1990-07-23 | 1992-02-06 | Pfizer Inc. | Derives de quinuclidine |
WO1992006079A1 (fr) * | 1990-09-28 | 1992-04-16 | Pfizer Inc. | Analogues cycliques d'heterocycles non aromatiques contenant de l'azote |
EP0499313A1 (fr) * | 1991-02-11 | 1992-08-19 | MERCK SHARP & DOHME LTD. | Composés azabicycliques, compositions pharmaceutiques les contenant et leur utilisation thérapeutique |
WO1992017449A1 (fr) * | 1991-03-26 | 1992-10-15 | Pfizer Inc. | Preparation stereoselective de piperidines substituees |
WO1992020676A1 (fr) * | 1991-05-22 | 1992-11-26 | Pfizer Inc. | 3-aminoquinuclidines substituees |
WO1993000330A2 (fr) * | 1991-06-21 | 1993-01-07 | Pfizer Inc. | Derives d'azanorbornane |
WO1993001170A1 (fr) * | 1991-07-01 | 1993-01-21 | Pfizer Inc. | Derives de 3-aminopiperidine et heterocycles associes contenant de l'azote |
Cited By (95)
Publication number | Priority date | Publication date | Assignee | Title |
---|---|---|---|---|
EP0627221A3 (fr) * | 1993-06-04 | 1995-08-02 | Pfizer | Antagonistes de la substance P pour le traitement du vomissement. |
EP0627221A2 (fr) * | 1993-06-04 | 1994-12-07 | Pfizer Inc. | Antagonistes de la substance P pour le traitement du vomissement |
WO1995007908A1 (fr) * | 1993-09-17 | 1995-03-23 | Pfizer Inc. | 3-benzylaminomethyl-piperidines a substitution heteroarylamino et heteroarylsulfonamido, et composes apparentes |
EP1209157A1 (fr) * | 1993-09-17 | 2002-05-29 | Pfizer Inc. | 3-Benzylaminométhyl-pipéridines à substitution hétéroarylamino et hétéroarylsulfonamido, et composés apparents |
US5703065A (en) * | 1993-09-17 | 1997-12-30 | Pfizer Inc. | Heteroarylamino and heteroarylsulfonamido substituted 3-benyzlaminomethyl piperidines and related compounds |
US5843966A (en) * | 1993-09-22 | 1998-12-01 | Glaxo Group Limited | Piperidine derivatives |
US5703240A (en) * | 1993-09-22 | 1997-12-30 | Glaxo Group Limited | Piperidine derivatives |
EP0653208A3 (fr) * | 1993-11-17 | 1995-10-11 | Pfizer | Antagonistes de la substance P pour le traitement et la prévention de l'erythème solaire. |
EP0653208A2 (fr) * | 1993-11-17 | 1995-05-17 | Pfizer Inc. | Antagonistes de la substance P pour le traitement et la prévention de l'erythème solaire |
EP0659409A3 (fr) * | 1993-11-23 | 1995-08-09 | Pfizer | Antagonistes de la substance P pour l'inhibition de l'angiogénése. |
EP0659409A2 (fr) * | 1993-11-23 | 1995-06-28 | Pfizer Inc. | Antagonistes de la substance P pour l'inhibition de l'angiogénése |
EP0655246A1 (fr) * | 1993-11-30 | 1995-05-31 | Pfizer Inc. | Antagonistes de la substance P pour le traitement des maladies causées par Helicobacter Pylori ou d'autres bacteries spirales, ureare-positives, gram-négatives |
WO1996029326A1 (fr) * | 1995-03-21 | 1996-09-26 | Glaxo Group Limited | 3-benzylamino-2-phenylpiperidines en tant qu'antagonistes de neurokinine |
US5919803A (en) * | 1995-03-21 | 1999-07-06 | Glaxo Group Limited | 3-benzylamino-2-phenylpiperidines as neurokinin antagonists |
AU696948B2 (en) * | 1995-03-27 | 1998-09-24 | Hisamitsu Pharmaceutical Co., Inc. | Piperidine derivatives |
US5886011A (en) * | 1995-03-27 | 1999-03-23 | Hisamitsu Pharmaceutical Co., Inc. | Piperidine derivatives as substance P antagonists |
WO1996030367A1 (fr) * | 1995-03-27 | 1996-10-03 | Hisamitsu Pharmaceutical Co., Inc. | Derives de piperidine |
WO1997003066A1 (fr) * | 1995-07-07 | 1997-01-30 | Pfizer Pharmaceuticals Inc. | Composes de benzolactam substitues utilises comme antagonistes de la substance p |
US6180647B1 (en) | 1995-07-07 | 2001-01-30 | Pfizer Inc. | Substituted benzolactam compounds as substance P antagonists |
EP0769300A2 (fr) | 1995-10-20 | 1997-04-23 | Pfizer Inc. | Médicament antiémétique contenant des Antagonistes des récepteurs NK-1 |
US6288225B1 (en) | 1996-05-09 | 2001-09-11 | Pfizer Inc | Substituted benzolactam compounds as substance P antagonists |
EP1080080A4 (fr) * | 1998-06-08 | 2001-03-07 | Advanced Medicine Inc | Nouveaux agents therapeutiques modulant les recepteurs de neurokinines |
EP1080080A1 (fr) * | 1998-06-08 | 2001-03-07 | Advanced Medicine, Inc. | Nouveaux agents therapeutiques modulant les recepteurs de neurokinines |
WO2000068224A1 (fr) * | 1999-05-06 | 2000-11-16 | Pfizer Products Inc. | Composes de benzolactame substitues |
EP1095655A2 (fr) * | 1999-10-25 | 2001-05-02 | Pfizer Products Inc. | Recepteurs antagonistes NK-1 et eletriptan pour le traitement de la migraine |
EP1095655A3 (fr) * | 1999-10-25 | 2003-03-26 | Pfizer Products Inc. | Recepteurs antagonistes NK-1 et eletriptan pour le traitement de la migraine |
US7119207B2 (en) * | 2000-04-10 | 2006-10-10 | Pfizer Inc | Benzoamide piperidine containing compounds and related compounds |
WO2001079153A1 (fr) * | 2000-04-19 | 2001-10-25 | Neurotech Co., Ltd. | Composes, compositions et procedes de prevention de la neurodegenerescence dans des atteintes lesionnelles aigues et chroniques au systeme nerveux central |
US6964982B2 (en) | 2000-04-20 | 2005-11-15 | Neurotech Co., Ltd. | Compounds, compositions and methods for preventing neurodegeneration in acute and chronic injuries in the central nervous system |
US6573402B1 (en) | 2000-04-20 | 2003-06-03 | Neurotech Co., Ltd. | Compounds, compositions and methods for preventing neurodegeneration in acute and chronic injuries in the central nervous system |
US8211877B2 (en) | 2000-04-20 | 2012-07-03 | Neurotech Pharmaceuticals Co., Ltd. | Compounds, compositions and methods for preventing neurodegeneration in acute and chronic injuries in the central nervous system |
US8211878B2 (en) | 2000-04-20 | 2012-07-03 | Neurotech Pharmaceuticals Co., Ltd. | Method for reducing neuronal death in nervous system injuries resulting from amyotrophic lateral sclerosis |
US7750045B2 (en) | 2000-04-20 | 2010-07-06 | Neurotech Pharmaceuticals Co., Ltd. | Compounds, compositions and methods for preventing neurodegeneration in acute and chronic injuries in the central nervous system |
EP1186318A3 (fr) * | 2000-09-06 | 2003-03-26 | Pfizer Products Inc. | Composition pour le traitement de la dépression et de l'anxieté contenant un antagoniste des recepteurs de 5HT 1 et un antagoniste du récepteur NK-1 |
EP1186318A2 (fr) * | 2000-09-06 | 2002-03-13 | Pfizer Products Inc. | Composition pour le traitement de la dépression et de l'anxieté contenant un antagoniste des recepteurs de 5HT 1 et un antagoniste du récepteur NK-1 |
EP1192952A3 (fr) * | 2000-09-28 | 2003-03-26 | Pfizer Products Inc. | Composition pour le traitement de la dépression et de l'anxieté contenant un antagoniste du recepteur NK-3 et un antagoniste du récepteur NK-1 |
EP1192952A2 (fr) * | 2000-09-28 | 2002-04-03 | Pfizer Products Inc. | Composition pour le traitement de la dépression et de l'anxieté contenant un antagoniste du recepteur NK-3 et un antagoniste du récepteur NK-1 |
WO2002028853A1 (fr) * | 2000-10-02 | 2002-04-11 | Tanabe Seiyaku Co., Ltd. | Compose de benzylamine, son procede de production et produit intermediaire correspondant |
US7186745B2 (en) | 2001-03-06 | 2007-03-06 | Astrazeneca Ab | Indolone derivatives having vascular damaging activity |
US7511074B2 (en) | 2002-06-19 | 2009-03-31 | Amkor Pharma, Inc. | Tetrafluorobenzyl derivatives and pharmaceutical composition for preventing and treating acute and chronic neurodegenerative diseases in central nervous system containing the same |
US7319160B2 (en) | 2002-06-19 | 2008-01-15 | Amkor Pharma, Inc. | Tetrafluorobenzyl derivatives and pharmaceutical composition for preventing and treating acute and chronic neurodegenerative diseases in central nervous system containing the same |
US7371896B2 (en) | 2002-06-19 | 2008-05-13 | Amkor Pharma, Inc. | Tetrafluorobenzyl derivatives and pharmaceutical composition for preventing and treating acute and chronic neurodegenerative diseases in central nervous system containing the same |
US7189878B2 (en) | 2002-06-19 | 2007-03-13 | Neurotech Co., Ltd. | Tetrafluorobenzyl derivatives and pharmaceutical composition for preventing and treating acute and chronic neurodegenerative diseases in central nervous system containing the same |
US9499531B2 (en) | 2004-07-15 | 2016-11-22 | Albany Molecular Research, Inc. | Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
US9085531B2 (en) | 2004-07-15 | 2015-07-21 | Albany Molecular Research, Inc. | Aryl- and heteroaryl-substituted tetrahydroisoquinolines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
WO2006123182A2 (fr) | 2005-05-17 | 2006-11-23 | Merck Sharp & Dohme Limited | Sulfones de cyclohexyle pour le traitement du cancer |
WO2007011820A2 (fr) | 2005-07-15 | 2007-01-25 | Amr Technology, Inc. | Tetrahydrobenzazepines substituees par aryle et heteroaryle, et leur utilisation pour bloquer la reabsorption de la noradrenaline, de la dopamine, et de la serotonine |
US9403776B2 (en) | 2005-07-15 | 2016-08-02 | Albany Molecular Research, Inc. | Aryl- and heteroaryl-substituted tetrahydrobenzazepines and use thereof to block reuptake of norepinephrine, dopamine, and serotonin |
WO2007041052A2 (fr) | 2005-09-29 | 2007-04-12 | Merck & Co., Inc. | Derives spiropiperidines acyles convenant comme modulateurs des recepteurs de la melanocortine-4 |
WO2007093827A1 (fr) | 2006-02-15 | 2007-08-23 | Istituto Di Ricerche Di Biologia Molecolare P. Angeletti Spa | Dérivés de trifluoroéthanone substitués par thiophène et thiazole en tant qu'inhibiteurs d'histone désacétylase (hdac) |
US8598383B2 (en) | 2006-04-13 | 2013-12-03 | Neurotech Pharmaceuticals Co., Ltd. | Pharmaceutical composition for treating or preventing degenerative and inflammatory diseases |
US8455470B2 (en) | 2006-04-13 | 2013-06-04 | Neurotech Pharmaceuticals Co., Ltd | Pharmaceutical composition for treating or preventing degenerative and inflammatory diseases |
EP2946778A1 (fr) | 2006-09-22 | 2015-11-25 | Merck Sharp & Dohme Corp. | Procédé de traitement utilisant des inhibiteurs de la synthèse d'acides gras |
EP2698157A1 (fr) | 2006-09-22 | 2014-02-19 | Merck Sharp & Dohme Corp. | Procédé de traitement utilisant des inhibiteurs de synthèse d'acide gras |
US11096950B2 (en) | 2006-11-01 | 2021-08-24 | Barbara Brooke Jennings | Compounds, methods, and treatments for abnormal signaling pathways for prenatal and postnatal development |
EP2336120A1 (fr) | 2007-01-10 | 2011-06-22 | Istituto di ricerche di Biologia Molecolare P. Angeletti S.R.L. | Combinaisons contenant indazoles à substitution amide utilisés comme inhibiteurs de la poly(ADP-ribose)polymérase (PARP) |
EP2805945A1 (fr) | 2007-01-10 | 2014-11-26 | MSD Italia S.r.l. | Indazoles substitués d'amide en tant qu'inhibiteurs PARP de poly(ADP-ribose)polymérase |
WO2008120653A1 (fr) | 2007-04-02 | 2008-10-09 | Banyu Pharmaceutical Co., Ltd. | Dérivé d'indoledione |
EP3103791A1 (fr) | 2007-06-27 | 2016-12-14 | Merck Sharp & Dohme Corp. | Dérivés de4-carboxybenzylamino utilisés comme inhibiteurs de l'histone désacétylase |
WO2009002495A1 (fr) | 2007-06-27 | 2008-12-31 | Merck & Co., Inc. | Dérivés de 4-carboxybenzylamino utilisés en tant qu'inhibiteurs de l'histone désacétylase |
US8686185B2 (en) | 2007-11-12 | 2014-04-01 | Neurotech Pharmaceuticals Co., Ltd. | Manufacturing method of 2-hydroxy-5-phenylalkylaminobenzoic acid derivatives and their salts |
WO2009111354A2 (fr) | 2008-03-03 | 2009-09-11 | Tiger Pharmatech | Inhibiteurs de la tyrosine kinase |
US9156812B2 (en) | 2008-06-04 | 2015-10-13 | Bristol-Myers Squibb Company | Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine |
US9498476B2 (en) | 2008-06-04 | 2016-11-22 | Albany Molecular Research, Inc. | Crystalline form of 6-[(4S)-2-methyl-4-(2-naphthyl)-1,2,3,4-tetrahydroisoquinolin-7-yl]pyridazin-3-amine |
WO2010090494A3 (fr) * | 2009-02-09 | 2011-01-06 | 주식회사 뉴로테크 | Utilisation médicale de dérivés d'acide 5-benzylaminosalicylique ou de sels correspondants |
WO2010114780A1 (fr) | 2009-04-01 | 2010-10-07 | Merck Sharp & Dohme Corp. | Inhibiteurs de l'activité akt |
WO2010132487A1 (fr) | 2009-05-12 | 2010-11-18 | Bristol-Myers Squibb Company | Formes cristallines de (s)-7-([1,2,4]triazolo[1,5-a] pyridin -6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline et leurs utilisations |
US9034899B2 (en) | 2009-05-12 | 2015-05-19 | Albany Molecular Research, Inc. | Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof |
US9604960B2 (en) | 2009-05-12 | 2017-03-28 | Albany Molecular Research, Inc. | Aryl, heteroaryl, and heterocycle substituted tetrahydroisoquinolines and use thereof |
WO2010132442A1 (fr) | 2009-05-12 | 2010-11-18 | Albany Molecular Reserch, Inc. | 7-([1,2, 4,]triazolo[1,5,-a]pyridine-6-yl)-4-(3,4-dichlorophényl)-1,2,3,4- tétrahydroisoquinoline et son utilisation |
US9173879B2 (en) | 2009-05-12 | 2015-11-03 | Bristol-Myers Squibb Company | Crystalline forms of (S)-7-([1,2,4]triazolo[1,5-a ]pyridin-6-yl)-4-(3,4-dichlorophenyl)-1,2,3,4-tetrahydroisoquinoline and use thereof |
WO2011046771A1 (fr) | 2009-10-14 | 2011-04-21 | Schering Corporation | Pipéridines substituées qui accroissent l'activité de p53, et utilisations de ces composés |
WO2011163330A1 (fr) | 2010-06-24 | 2011-12-29 | Merck Sharp & Dohme Corp. | Nouveaux composés hétérocycliques utilisés comme inhibiteurs de erk |
EP3330377A1 (fr) | 2010-08-02 | 2018-06-06 | Sirna Therapeutics, Inc. | Inhibition à médiation par interférence arn de caténine (protéine associée à cadhérine), expression du gène bêta 1 (ctnnb1) à l'aide de petit acide nucléique interférent (sian) |
WO2012018754A2 (fr) | 2010-08-02 | 2012-02-09 | Merck Sharp & Dohme Corp. | Inhibition à médiation par interférence arn de caténine (protéine associée à cadhérine), expression du gène bêta 1 (ctnnb1) à l'aide de petit acide nucléique interférent (sian) |
EP4079856A1 (fr) | 2010-08-17 | 2022-10-26 | Sirna Therapeutics, Inc. | Inhibition médiée par des arn interférents de l'expression génique du virus de l'hépatite b (vhb) à l'aide de petits acides nucléiques interférents (pani) |
WO2012027236A1 (fr) | 2010-08-23 | 2012-03-01 | Schering Corporation | Nouveaux dérivés de pyrazolo[1,5-a]pyrimidine utilisés comme inhibiteurs de mtor |
WO2012030685A2 (fr) | 2010-09-01 | 2012-03-08 | Schering Corporation | Dérivés d'indazole utilisables en tant qu'inhibiteurs de la voie erk |
WO2012036997A1 (fr) | 2010-09-16 | 2012-03-22 | Schering Corporation | Dérivés condensés de pyrazole utilisés comme nouveaux inhibiteurs erk |
EP3327125A1 (fr) | 2010-10-29 | 2018-05-30 | Sirna Therapeutics, Inc. | Inhibition au moyen d'interférence arn d'une expression de gène utilisant des acides nucléiques à petit interférent (sina) |
EP3766975A1 (fr) | 2010-10-29 | 2021-01-20 | Sirna Therapeutics, Inc. | Inhibition au moyen d'interférence arn d'une expression de gène utilisant des acides nucléiques à petit interférent (sina) |
WO2012087772A1 (fr) | 2010-12-21 | 2012-06-28 | Schering Corporation | Dérivés d'indazole utiles en tant qu'inhibiteurs de erk |
WO2012145471A1 (fr) | 2011-04-21 | 2012-10-26 | Merck Sharp & Dohme Corp. | Inhibiteurs du récepteur du facteur de croissance 1 analogue à l'insuline |
WO2013063214A1 (fr) | 2011-10-27 | 2013-05-02 | Merck Sharp & Dohme Corp. | Nouveaux composés qui sont des inhibiteurs d'erk |
WO2013165816A2 (fr) | 2012-05-02 | 2013-11-07 | Merck Sharp & Dohme Corp. | Compositions de petit acide nucléique interférent (sina) |
EP3919620A1 (fr) | 2012-05-02 | 2021-12-08 | Sirna Therapeutics, Inc. | Compositions d'acide nucléique interférent court (sina) |
WO2014052563A2 (fr) | 2012-09-28 | 2014-04-03 | Merck Sharp & Dohme Corp. | Nouveaux composés inhibiteurs de erk |
WO2014085216A1 (fr) | 2012-11-28 | 2014-06-05 | Merck Sharp & Dohme Corp. | Compositions et procédés pour traiter le cancer |
WO2014100065A1 (fr) | 2012-12-20 | 2014-06-26 | Merck Sharp & Dohme Corp. | Imidazopyridines substituées en tant qu'inhibiteurs de hdm2 |
WO2014120748A1 (fr) | 2013-01-30 | 2014-08-07 | Merck Sharp & Dohme Corp. | Purines 2,6,7,8-substituées utilisées en tant qu'inhibiteurs de hdm2 |
WO2015034925A1 (fr) | 2013-09-03 | 2015-03-12 | Moderna Therapeutics, Inc. | Polynucléotides circulaires |
WO2019094311A1 (fr) | 2017-11-08 | 2019-05-16 | Merck Sharp & Dohme Corp. | Inhibiteurs de prmt5 |
WO2020033284A1 (fr) | 2018-08-07 | 2020-02-13 | Merck Sharp & Dohme Corp. | Inhibiteurs de prmt5 |
WO2020033282A1 (fr) | 2018-08-07 | 2020-02-13 | Merck Sharp & Dohme Corp. | Inhibiteurs de prmt5 |
WO2020136441A1 (fr) * | 2018-12-28 | 2020-07-02 | Gnt Pharma Co., Ltd. | Compositions et méthodes de traitement de troubles neurodégénératifs |
Also Published As
Publication number | Publication date |
---|---|
CN1092771A (zh) | 1994-09-28 |
DK0675886T3 (da) | 2000-09-18 |
FI935529A (fi) | 1994-06-11 |
CA2150123C (fr) | 2004-12-07 |
JP2722279B2 (ja) | 1998-03-04 |
JPH1095780A (ja) | 1998-04-14 |
DE69328975D1 (de) | 2000-08-10 |
AU5169693A (en) | 1994-07-04 |
EP0806423A1 (fr) | 1997-11-12 |
CA2150123A1 (fr) | 1994-06-23 |
EP0675886B1 (fr) | 2000-07-05 |
JPH07509490A (ja) | 1995-10-19 |
ES2147759T3 (es) | 2000-10-01 |
IL107843A0 (en) | 1994-04-12 |
MX9307810A (es) | 1994-07-29 |
GR3034329T3 (en) | 2000-12-29 |
FI935529A0 (fi) | 1993-12-09 |
PT675886E (pt) | 2000-12-29 |
ATE194340T1 (de) | 2000-07-15 |
DE69328975T2 (de) | 2000-11-09 |
EP0675886A1 (fr) | 1995-10-11 |
JP3165401B2 (ja) | 2001-05-14 |
Similar Documents
Publication | Publication Date | Title |
---|---|---|
CA2150123C (fr) | Derives de substitution aminomethylene d'heterocycles non aromatiques | |
US5703065A (en) | Heteroarylamino and heteroarylsulfonamido substituted 3-benyzlaminomethyl piperidines and related compounds | |
US5721255A (en) | Substituted benzylamino nitrogen containing non-aromatic heterocycles | |
US9815797B2 (en) | Fused bicyclic heteroaromatic derivatives as modulators of TNF activity | |
JP6453334B2 (ja) | Tnf活性のモジュレーターとしてのイミダゾピリジン誘導体 | |
CA2930142C (fr) | Derives de tetrahydrobenzimidazole substitues comme modulateurs de l'activite du tnf-a | |
JP2002541103A (ja) | ピロリジン系ケモカイン受容体活性調節剤 | |
JPH11502861A (ja) | サブスタンスpアンタゴニストとしての置換ベンゾラクタム化合物 | |
US20100190768A1 (en) | Novel fused pyrole derivative | |
NZ536477A (en) | Tetrahydropyranyl cyclopentyl tetrahydropyridopyridine modulators of chemokine receptor activity | |
WO2004041161A2 (fr) | Modulateurs de l'activite des recepteurs de la chimiokine a base de tetrahydropyranyl-cyclopentyl-benzylamide | |
KR20010014262A (ko) | 신규 나프티리딘 유도체 또는 그 염 | |
AU630397B2 (en) | 4,5,6,7-tetrahydrobenzimidazole derivatives | |
CS29792A3 (en) | N-(aryloxyalkyl)heteroaryl-8-azabicyclo/3.2.1/ octanes, intermediatesthereof and process of their preparation and use as medicaments | |
WO2005067502A2 (fr) | Modulateurs d'amide cyclopentyle d'alkylamino, arylamino et sulfonamido de l'activite des recepteurs de la chimiokine | |
KR100235285B1 (ko) | 브라디키닌 길항근으로서 디하이드로피리딘 유도체 | |
US6369074B1 (en) | Aminomethylene substituted non-aromatic heterocycles and use as substance P antagonists | |
US5854262A (en) | Aminomethylene substituted non-aromatic heterocycles and use as substance P antagonists | |
US20010023248A1 (en) | Aminomethylene substituted non-aromatic heterocycles and use as substance P antagonists | |
KR19990022265A (ko) | 항정신병제로서의 피리딘이미닐-1,2-벤즈이속사졸 및-벤즈이소티아졸 | |
JP2003502315A (ja) | ケモカインレセプター活性のn−シクロペンチルモジュレーター | |
CA2171972C (fr) | Derives de substitution heteroarylamino et heteroarylsulfonamido de 3-benzylaminomethylpiperidines et composes apparentes | |
AU6428400A (en) | Tricyclic analgesics | |
JP2000038386A (ja) | 新規ナフチリジン誘導体またはその塩 |
Legal Events
Date | Code | Title | Description |
---|---|---|---|
AK | Designated states |
Kind code of ref document: A1 Designated state(s): AU CA JP KR NO NZ US |
|
AL | Designated countries for regional patents |
Kind code of ref document: A1 Designated state(s): AT BE CH DE DK ES FR GB GR IE IT LU MC NL PT SE |
|
DFPE | Request for preliminary examination filed prior to expiration of 19th month from priority date (pct application filed before 20040101) | ||
121 | Ep: the epo has been informed by wipo that ep was designated in this application | ||
WWE | Wipo information: entry into national phase |
Ref document number: 2150123 Country of ref document: CA |
|
WWE | Wipo information: entry into national phase |
Ref document number: 08522230 Country of ref document: US |
|
WWE | Wipo information: entry into national phase |
Ref document number: 1993922821 Country of ref document: EP |
|
WWP | Wipo information: published in national office |
Ref document number: 1993922821 Country of ref document: EP |
|
WWG | Wipo information: grant in national office |
Ref document number: 1993922821 Country of ref document: EP |